The risk of hypoglycemia is one of the major obstacles in the optimum treatment in both type 1 (1,2) and type 2 (3) diabetes, as well as in patients in intensive care units (4). Furthermore, in addition to short-term risks, including death, hypoglycemia also produces long-term health consequences including a substantial risk of death from cardiovascular events (5). Thus therapies to minimize the risk of hypoglycemia could have a profound impact on public health (2). The main cause of hypoglycemia is a failure in the counterregulatory autonomic and endocrine responses that normally act to correct low blood glucose (2). Failure in counterregulatory responses is caused by antecedent hypoglycemia itself and is therefore referred to as hypoglycemia-induced autonomic failure (2). Counterregulatory responses are mediated by glucose-inhibited neurons in the ventromedial nucleus (VMN) of the hypothalamus (6,7). Specifically, inhibiting glucose metabolism in neurons in the VMN of the hypothalamus induces systemic counterregulatory responses (6), whereas inhibiting glutamate neurotransmission in Sf1 neurons (confined to the VMN) impairs counterregulatory responses (7).

Szepietowska et al. (8) now report an unexpected mechanism regulating counterregulatory responses that may also contribute to counterregulatory failure: the EphA5-ephrin signaling system. Ephrins were discovered in a search for tyrosine kinase receptor homologs that might contribute to oncogenesis (9) by screening for homology to the oncogene v-fps. The resulting gene was highly overexpressed in an …